1. Field of the Invention
This invention relates to therapeutic agents and more particularly, to pharmaceutical compositions and preparations containing the analgesic and non-steroidal antiinflammatory compound, ibuprofen. These compositions are extensively used and are of great value in the treatment of pain and inflammation, particularly in reducing discomfort from various types of arthritis. The chemical formulation for ibuprofen is (.+-.)-2-(P-Isobutylphenyl) propionic acid [Ibuprofen] and S-(+)-2-(p-Isobutylphenyl] propionic acid [S(+)-ibuprofen] and are normally supplied in crystalline form. However, it has been found that crystalline ibuprofen normally received commercially from chemical suppliers cakes easily and exhibits poor flow properties, particularly after storage over a long period of time. Accordingly, when used without any further treatment in tableting and capsule-filling equipment for which acceptable powder flow characteristics are essential to product processing, significant caking and other flow problems may arise, both during transfer of the ibuprofen from one place to another and during the tableting or capsule-filling process. Consequently, it has been found expedient to combine the raw ibuprofen with pharmaceutically acceptable excipients to form granules containing from about 50 to about 90 percent by weight ibuprofen. These granules exhibit much better hardness and free-flowing properties and characteristics than the unmixed, commercially-available crystalline ibuprofen and are more stable over a longer period of time.
It is therefore desirable to formulate ibuprofen particles which exhibit satisfactory free-flowing characteristics in order to more efficiently and expeditiously manufacture ibuprofen tablets and capsules. This objective is achieved in a first embodiment by mixing the commercial grade ibuprofen powder or crystals with a hydrophilic solvent such as hot water. In a second embodiment the ibuprofen is mixed with a mixture of a hydrophilic solvent such as water and one or more hydrophobic solvents, such as acetone, methyl alcohol, ethyl alcohol, isopropyl alcohol and N-propyl alcohol, the latter group of which are miscible with water. In a third embodiment of the invention, the ibuprofen is mixed with one or more of the hydrophobic organic solvents innumerated above, to create a more free-flowing ibuprofen product. The granulating liquid operates in each case to melt or partially dissolve and change the shape of at least the surface crystalline structure of the ibuprofen particles from a flow-retarding, generally rectangular shape to a free-flowing and easily compressible cubic or irregular configuration. In the case of a granulating liquid containing both a hydrophilic and one or more hydrophobic solvents, mixing is conducted at a temperature in the range of from about 20.degree. C. to about 100.degree. C. and the ratio of concentration of the hydrophilic solvent to the hydrophobic solvent may range from 0.5 to 99.5, depending upon the chosen material source, equipment used and process conditions.
In a fourth embodiment of the invention, direct compressible ibuprofen particles having superior dry flow characteristics are prepared by mixing commercially available, dry ibuprofen with micron size amorphous silica gel (SiO.sub.2) in a weight percent of from about 0.05 to about 5.0 percent of the weight of the ibuprofen. The silica gel component acts to coat, and therefore minimize adhesion, of the ibuprofen particles, and may be used in any one of several commercially available materials, including "fumed", or synthetic silica or a coagulated aerosol of synthetic silica, in non-exclusive particular.
2. Description of the Prior Art
Various ibuprofen compositions, as well as processes of manufacture and purification, are well known in the art.
European Patent Application No. 0241126, entitled "Therapeutic Agents" details a solid pharmaceutical composition which includes granules consisting of an aggregate of ibuprofen crystals which have advantageous free flowing, compression and formulation properties. The solid composition is essentially non-friable and includes no excipents. However, solid dosage formulations produced by mixing a composition according to the invention with appropriate formulation excipients, may also be prepared. The median crystalline particle size of the crystalline ibuprofen prepared according to the invention is said to be in the range of 5-100 microns and damp ibuprofen is preferred for employment in a wet granulation process to formulate the solid ibuprofen composition.
European Patent Application No. 172014 relates to a granular pharmaceutical composition which includes ibuprofen. The application states that in order to effect effective disintegration of the compacted granules in the dosage forms, the granules must contain an excipient, which is identified as croscarmellose sodium. The granules disclosed contain about 85-99 percent by weight ibuprofen and from about 1 percent to about 15 percent by weight croscarmellose sodium.
Japanese Patent Application No. 120,616 also relates to granular pharmaceutical compositions which include ibuprofen. The patent details a process by which the desired granules may be produced by heat melting ibuprofen powder and subsequently cooling the powder until the melt is solidified, after which the solid melt is crushed into granules. The patent notes that the process is time-consuming, particularly in the cooling stage, wherein the resulting granules are characterized by solid blocks of crystalline ibuprofen.
U.S. Pat. No. 4,690,834, entitled "Process for Coating Solid Particles" details a process for coating solid particles using a material which is highly viscous or solid at room temperature. The coating material and particulate material to be coated are introduced into a mixing disc apparatus, where the coating material forms a finely divided mist for coating the particulate material.
U.S. Pat. No. 4,911,921, entitled "High Ibuprofen Content Granulations", details a granular pharmaceutical composition containing 85-99 percent ibuprofen, 0.9 to about 15.0 percent binder and 0.1 to about 5.0 percent polyvinylpyrrolidone, wherein the polyvinylpyrrolidone defines a film with a portion of the binder to form agglomerates. Ibuprofen may be fluidized with a portion of the binder in a fluid bed apparatus and sprayed with aqueous dispersion of polyvinylpyrrolidone and the remainder of the binder. This granulation may be subsequently blended with additional excipients and, optionally, additional active pharmaceutical ingredients, for direct compression into tablets.
U.S. Pat. No. 4,904,477, entitled "Spray Dried Ibuprofen Compositions", is drawn to a spray dried ibuprofen composition suitable for direct compression into tablets and including a spray dried dispersion in water of ibuprofen, pregalatinized starch, a disintegrate and a wetting agent for the ibuprofen.
U.S. Pat. No. 4,994,604, entitled "Formation and Resolution of Ibuprofen Lysinate; Salt Formation In Aqueous-Organic Solvent Mixture Followed by Preferential Crystallization", details a process for the formation and resolution of (S) ibuprofen-(S) -lysine by preferential crystalization to separate a pair of diasteromeric salts, (S) ibuprofen- (S)- lysine and (R)- ibuprofen- (S)- lysine.
It is an object of this invention to provide a process for producing direct compressible ibuprofen which is suitable for mixing with various pharmaceutically-acceptable excipients and compression into tablets or filling capsules, by granulating commercial grade ibuprofen with a hydrophilic solvent such as water at 25.degree. C. to 85.degree. C., or a mixture of hydrophilic and hydrophobic solvents, or hydrophobic solvent(s), to alter the crystalline surface of the ibuprofen.
Another object of this invention is to provide a method for producing direct compressible ibuprofen particles which are suitable for mixing with various pharmaceutically acceptable excipients and compression into tablets or filling capsules, which method includes mixing 100 parts of commercially available, dry ibuprofen with 10 to 30 parts of a mixture of hydrophobic and hydrophilic solvents, wherein the crystalline surface of the ibuprofen is first dissolved by one or more hydrophobic solvents such as acetone, methyl alcohol, ethyl alcohol, isopropyl alcohol and N-propyl alcohol, in non-exclusive particular, and then recrystallize by the hydrophilic solvent component such as pharmaceutically acceptable water, to produce favorable ibuprofen dry flow characteristics.
Yet another object of this invention is to provide a method or process for producing direct compressible ibuprofen which is suitable for mixing with various pharmaceutically-acceptable excipients and compression into tablets and filling capsules, by mixing commercial grade ibuprofen with a hydrophobic organic solvent or combination of organic solvents selected from the group, acetone, methyl alcohol, ethyl alcohol, isopropyl alcohol and N-propyl alcohol, in non-exclusive particular, in a ratio of ibuprofen powder 100 parts to solvent 10 to 30 parts by weight, in which the crystalline surface of the ibuprofen is dissolved by the solvent and recrystallized slowly into an ibuprofen crystalline structure having favorable dry flow characteristics after evaporation of the solvent or solvents.
Still another object of the invention is to provide a method or process for producing direct compressible ibuprofen particles which are suitable for combination with other pharmaceutically acceptable excipients and compression into tablets or filling capsules, by mixing 100 parts of commercial grade ibuprofen with 10 to 30 parts of a hydrophilic solvent such as pharmaceutically acceptable water at a temperature in the range of from about 25.degree. C. to about 85.degree. C., wherein the crystalline surface of ibuprofen is then instantaneously melted and recrystallized in a mixing bed to form a desirable surface for direct compression or capsule-filling purposes.
Another object of this invention is to provide a method for producing direct compressible ibuprofen from commercially available, dry ibuprofen, which method includes mixing the dry ibuprofen with a micron size, amphorous silica gel (SiO.sub.2) to facilitate coating the dry ibuprofen particles with silica gel and realizing desirable free-flowing characteristics of the coated ibuprofen particles.
Still another object of this invention is to provide a method for providing direct compressible ibuprofen particles from commercially available, dry ibuprofen, which includes coating the dry ibuprofen with either a coagulated aerosol of synthetic silica gel or a hydrophilic, fumed (pyrogenic) silica gel or micron size amorphous silica gel to facilitate coating of the flow-inhibiting crystalline structure of the dry ibuprofen into free-flowing, coated ibuprofen particles which are suitable for mixing with selected pharmaceutically acceptable excipients and direct compression into tablets or filling capsules.